The Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, 11937 US HWY 271, Biomedical Research Building, Lab C-5, Tyler, TX 75708, USA.
Am J Respir Cell Mol Biol. 2010 Jun;42(6):685-96. doi: 10.1165/rcmb.2008-0433OC. Epub 2009 Jul 27.
Malignant pleural mesothelioma (MPM) is a lethal neoplasm for which current therapy is unsatisfactory. The urokinase plasminogen activator receptor (uPAR) is associated with increased virulence of many solid neoplasms, but its role in the pathogenesis of MPM is currently unclear. We found that REN human pleural MPM cells expressed 4- to 10-fold more uPAR than MS-1 or M9K MPM cells or MeT5A human pleural mesothelial cells. In a new orthotopic murine model of MPM, we found that the kinetics of REN cell tumorigenesis is accelerated versus MS-1 or M9K cells, and that REN instillates generated larger tumors expressing increased uPAR, were more invasive, and caused earlier mortality. While REN, MS-1, and M9K tumors were all associated with prominent extravascular fibrin deposition, excised REN tumor homogenates were characterized by markedly increased uPAR at both the mRNA and protein levels. REN cells exhibited increased thymidine incorporation, which was attenuated in uPAR-silenced cells (P < 0.01). REN cells traversed three-dimensional fibrin gels while MS-1, M9K, and MeT5A cells did not. uPAR siRNA or uPAR blocking antibodies decreased REN cell migration and invasion, while uPA and fetal bovine serum augmented the effects. Transfection of relatively low uPAR expressing MS-1 cells with uPAR cDNA increased proliferation and migration in vitro and tumor formation in vivo. These observations link overexpression of uPAR to the pathogenesis of MPM, demonstrate that this receptor contributes to accelerated tumor growth in part through interactions with uPA, and suggest that uPAR may be a promising target for therapeutic intervention.
恶性胸膜间皮瘤（MPM）是一种致命的肿瘤，目前的治疗效果并不令人满意。尿激酶型纤溶酶原激活物受体（uPAR）与许多实体瘤的侵袭性增加有关，但它在 MPM 发病机制中的作用尚不清楚。我们发现，REN 人胸膜间皮瘤细胞比 MS-1 或 M9K 间皮瘤细胞或 MeT5A 人胸膜间皮细胞表达的 uPAR 高出 4 到 10 倍。在一种新的 MPM 原位小鼠模型中，我们发现 REN 细胞的肿瘤发生动力学比 MS-1 或 M9K 细胞更快，REN 细胞的注入导致更大的肿瘤，表达更高的 uPAR，具有更强的侵袭性，并导致更早的死亡率。虽然 REN、MS-1 和 M9K 肿瘤都与明显的血管外纤维蛋白沉积有关，但切除的 REN 肿瘤匀浆的 uPAR 在 mRNA 和蛋白质水平上都明显增加。REN 细胞表现出更高的胸苷掺入，而沉默 uPAR 的细胞则减少（P < 0.01）。REN 细胞穿过三维纤维蛋白凝胶，而 MS-1、M9K 和 MeT5A 细胞则不能。uPAR siRNA 或 uPAR 阻断抗体降低了 REN 细胞的迁移和侵袭，而 uPA 和胎牛血清则增强了这些作用。低表达 uPAR 的 MS-1 细胞转染 uPAR cDNA 后，体外增殖和迁移以及体内肿瘤形成增加。这些观察结果将 uPAR 的过表达与 MPM 的发病机制联系起来，表明该受体通过与 uPA 的相互作用部分促进了肿瘤的快速生长，并表明 uPAR 可能是治疗干预的一个有前途的靶点。
